Quality control of the mitochondrial proteome Song, Jiyao; Herrmann, Johannes M; Becker, Thomas
Nature reviews. Molecular cell biology,
01/2021, Letnik:
22, Številka:
1
Journal Article
Recenzirano
Mitochondria contain about 1,000-1,500 proteins that fulfil multiple functions. Mitochondrial proteins originate from two genomes: mitochondrial and nuclear. Hence, proper mitochondrial function ...requires synchronization of gene expression in the nucleus and in mitochondria and necessitates efficient import of mitochondrial proteins into the organelle from the cytosol. Furthermore, the mitochondrial proteome displays high plasticity to allow the adaptation of mitochondrial function to cellular requirements. Maintenance of this complex and adaptable mitochondrial proteome is challenging, but is of crucial importance to cell function. Defects in mitochondrial proteostasis lead to proteotoxic insults and eventually cell death. Different quality control systems monitor the mitochondrial proteome. The cytosolic ubiquitin-proteasome system controls protein transport across the mitochondrial outer membrane and removes damaged or mislocalized proteins. Concomitantly, a number of mitochondrial chaperones and proteases govern protein folding and degrade damaged proteins inside mitochondria. The quality control factors also regulate processing and turnover of native proteins to control protein import, mitochondrial metabolism, signalling cascades, mitochondrial dynamics and lipid biogenesis, further ensuring proper function of mitochondria. Thus, mitochondrial protein quality control mechanisms are of pivotal importance to integrate mitochondria into the cellular environment.
Mitochondrial biogenesis requires the import of a large number of precursor proteins from the cytosol. Although specific membrane-bound preprotein translocases have been characterized in detail, it ...was assumed that protein transfer from the cytosol to mitochondria mainly involved unselective binding to molecular chaperones. Recent findings suggest an unexpected versatility of protein transfer to mitochondria. Cytosolic factors have been identified that bind to selected subsets of preproteins and guide them to mitochondrial receptors in a post-translational manner. Cotranslational import processes are emerging. Mechanisms for crosstalk between protein targeting to mitochondria and other cell organelles, in particular the endoplasmic reticulum (ER) and peroxisomes, have been uncovered. We discuss how a network of cytosolic machineries and targeting pathways promote and regulate preprotein transfer into mitochondria.
The majority of mitochondrial proteins are targeted to mitochondria upon the completion of protein synthesis at cytosolic ribosomes (post-translational translocation). A network of chaperones, cochaperones, and further cytosolic factors guides preproteins to the translocase of the mitochondrial outer membrane.Cochaperones such as J-proteins provide selectivity for subgroups of mitochondrial preproteins and bind to specific receptors on the mitochondrial surface.mRNAs and cytosolic ribosomes can associate with the mitochondrial outer membrane. Several mitochondrial proteins are imported in a cotranslational manner via association of ribosome–nascent chain complexes with the translocase of the outer membrane.The targeting pathways of some preproteins to mitochondria, ER, and peroxisomes are in functional crosstalk and can share cytosolic factors.The regulation of cytosolic factors and targeting pathways provides a means of adapting organelle biogenesis to metabolism and environmental cues.
Mitochondrial biogenesis and functions depend on the import of precursor proteins via the 'translocase of the outer membrane' (TOM complex). Defects in protein import lead to an accumulation of ...mitochondrial precursor proteins that induces a range of cellular stress responses. However, constitutive quality-control mechanisms that clear trapped precursor proteins from the TOM channel under non-stress conditions have remained unknown. Here we report that in Saccharomyces cerevisiae Ubx2, which functions in endoplasmic reticulum-associated degradation, is crucial for this quality-control process. A pool of Ubx2 binds to the TOM complex to recruit the AAA ATPase Cdc48 for removal of arrested precursor proteins from the TOM channel. This mitochondrial protein translocation-associated degradation (mitoTAD) pathway continuously monitors the TOM complex under non-stress conditions to prevent clogging of the TOM channel with precursor proteins. The mitoTAD pathway ensures that mitochondria maintain their full protein-import capacity, and protects cells against proteotoxic stress induced by impaired transport of proteins into mitochondria.
The translocase of the outer mitochondrial membrane (TOM) is the main entry gate for proteins
. Here we use cryo-electron microscopy to report the structure of the yeast TOM core complex
at 3.8-Å ...resolution. The structure reveals the high-resolution architecture of the translocator consisting of two Tom40 β-barrel channels and α-helical transmembrane subunits, providing insight into critical features that are conserved in all eukaryotes
. Each Tom40 β-barrel is surrounded by small TOM subunits, and tethered by two Tom22 subunits and one phospholipid. The N-terminal extension of Tom40 forms a helix inside the channel; mutational analysis reveals its dual role in early and late steps in the biogenesis of intermembrane-space proteins in cooperation with Tom5. Each Tom40 channel possesses two precursor exit sites. Tom22, Tom40 and Tom7 guide presequence-containing preproteins to the exit in the middle of the dimer, whereas Tom5 and the Tom40 N extension guide preproteins lacking a presequence to the exit at the periphery of the dimer.
Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and ...how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in ADP/ATP translocase 1 (ANT1), and its yeast homolog ADP/ATP carrier 2 (Aac2), cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis, and cell viability independent of ANT1's nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/ANT1 causes severe clogging primarily at the translocase of the outer membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger ANT1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy ANT1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.
Mitochondria possess elaborate machineries for the import of proteins from the cytosol. Cytosolic factors like Hsp70 chaperones and their co-chaperones, the J-proteins, guide proteins to the ...mitochondrial surface. The translocase of the mitochondrial outer membrane (TOM) forms the entry gate for preproteins. How the proteins are delivered to mitochondrial preprotein receptors is poorly understood. We identify the cytosolic J-protein Xdj1 as a specific interaction partner of the central receptor Tom22. Tom22 recruits Xdj1 to the mitochondrial surface to promote import of preproteins and assembly of the TOM complex. Additionally, we find that the receptor Tom70 binds a different cytosolic J-protein, Djp1. Our findings suggest that cytosolic J-proteins target distinct TOM receptors and promote the biogenesis of mitochondrial proteins.
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•The receptor Tom22 recruits the cytosolic J-protein Xdj1 to mitochondria•Xdj1 delivers preproteins to Tom22 and promotes biogenesis of the TOM complex•The receptor Tom70 recruits a different cytosolic J-protein, Djp1•Mitochondrial receptors selectively recognize cytosolic J-protein co-chaperones
Opaliński et al. report that mitochondrial protein import receptors selectively recognize J-protein co-chaperones of the cytosol. The co-chaperones bind hydrophobic precursor proteins and assist in transferring them to the receptors of the mitochondrial protein entry gate.
Abstract
The mitochondrial F
1
F
O
-ATP synthase produces the bulk of cellular ATP. The soluble F
1
domain contains the catalytic head that is linked via the central stalk and the peripheral stalk to ...the membrane embedded rotor of the F
O
domain. The assembly of the F
1
domain and its linkage to the peripheral stalk is poorly understood. Here we show a dual function of the mitochondrial Hsp70 (mtHsp70) in the formation of the ATP synthase. First, it cooperates with the assembly factors Atp11 and Atp12 to form the F
1
domain of the ATP synthase. Second, the chaperone transfers Atp5 into the assembly line to link the catalytic head with the peripheral stalk. Inactivation of mtHsp70 leads to integration of assembly-defective Atp5 variants into the mature complex, reflecting a quality control function of the chaperone. Thus, mtHsp70 acts as an assembly and quality control factor in the biogenesis of the F
1
F
O
-ATP synthase.
Fidelity of organellar protein targeting Song, Jiyao; Becker, Thomas
Current opinion in cell biology,
April 2022, 2022-Apr, 2022-04-00, 20220401, Letnik:
75
Journal Article
Recenzirano
The majority of cellular proteins are targeted to organelles. Cytosolic ribosomes produce these proteins as precursors with cleavable or non-cleavable targeting sequences that direct them to receptor ...proteins on the organelle surface. Multiple targeting factors ensure cellular sorting of the precursor proteins. In co-translational protein import, the ribosome-nascent chain complex is transported to the organellar protein translocase to couple protein synthesis and protein import. In post-translational mode, targeting factors like molecular chaperones guide the precursor proteins from ribosomes to the cell organelle. Defects in protein targeting and import cause mistargeting of proteins to different cellular compartments and challenge the balance of cellular proteostasis. Specific dislocases and degradation machineries remove such mislocalized proteins from the membrane to allow retargeting or their proteasomal turnover. In this review, we discuss targeting and quality control factors that ensure fidelity of protein targeting to mitochondria.
Assembling themitochondrial ATP synthase Song, Jiyao; Pfanner, Nikolaus; Becker, Thomas
Proceedings of the National Academy of Sciences - PNAS,
03/2018, Letnik:
115, Številka:
12
Journal Article
Assembling the mitochondrial ATP synthase Song, Jiyao; Pfanner, Nikolaus; Becker, Thomas
Proceedings of the National Academy of Sciences - PNAS,
2018-Mar-20, Letnik:
115, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Mitochondria are known as the powerhouses of the cell. The F1Fo-ATP synthase of the mitochondrial inner membrane produces the bulk of cellular ATP. The respiratory chain complexes pump protons across ...the inner membrane into the intermembrane space and thereby generate a proton-motive force that drives the ATP synthase. In a fascinating molecular mechanism, the ATP synthase couples the synthesis of ATP to the transport of protons into the matrix. Formation of the ATP synthase depends on the association of 17 different structural subunits of dual genetic origin. Whereas a number of assembly factors and steps have been identified in the model organism baker's yeast, little has been known about the assembly of the human ATP synthase.
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